Imaging mass cytometry reveals novel cellular neighbourhoods predicting prognosis of non-alcoholic fatty liver disease-associated hepatocellular carcinoma

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Abstract
Objective Nonalcoholic fatty liver disease (NAFLD) is increasingly implicated in hepatocellular carcinoma (HCC) pathogenesis. We aimed to examine panoramic cellular composition and spatial structure of NAFLD-HCC clinical samples, assess the role of tumor micro-environment (TME) in the process of liver fibrosis and oncogenesis, and find potential clinical intervention measures. Methods Imaging mass cytometry (IMC) technology was used to reveal the expression and spatial distribution of biomarkers in samples from 56 patients with NAFLD-HCC and 6 patients with focal nodular hyperplasia as control. 37 different metal coupling biomarkers were designed to label the tumor, border and adjacent regions of the tissues to generate 367 highly multiplexed histology images at single-cell resolution. By integrating the expression levels of biomarkers with the relative positional relationships between cells, we defined functional units as tightly interacting cellular neighborhoods (CNs). The relationship between CNs and patients’ prognosis was then accessed to identify potential clinical targets of NAFLD-HCC. Results Cells were dimensionally reduced to access the cellular phenotype and 18 clusters of cells and 9 CNs were defined. Heterogeneity in TME and CN composition was observed not only across various regions within the same individual but also among comparable regions in different patients. The combined analysis of the overall survival data revealed that patients with a high enrichment of T & NK cell associated CN exhibited a more favorable clinical prognosis. In contrast, those with a high enrichment of myofibroblast associated CN and a YAP+ cancer cell associated CN exhibited a poor clinical prognosis. Conclusion Our study provided a landscape of NAFLD-HCC and its TME characteristics from the topological perspective. The findings indicated that changing the low immune cell infiltration status of NAFLD-HCC through the augmentation of active T and NK cells and hepatic antifibrotic therapy may benefit the long-term prognosis of patients with NAFLD-HCC. Key words: imaging mass cytometry, NAFLD-HCC, cellular neighborhoods, prognosis, tumor micro-environment

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